Case report

Atypical clinical
course in juvenile
metachromatic
leukodystrophy
involving novel
arylsulfatase A gene
mutations
Banu Anlar* MD, Hacettepe University Faculty of Medicine,
Department of Paediatric Neurology, Ankara, Turkey.
John S Waye PhD, Department of Pathology and Molecular
Medicine, McMaster University;
Barry Eng BSc, Molecular Diagnostic Genetics, Hamilton
Regional Laboratory Medicine Program, McMaster
University Medical Centre, Hamilton, Ontario, Canada.
Kader Karli Oguz MD, Hacettepe University Faculty of
Medicine, Department of Radiology, Ankara, Turkey.
*Correspondence to first author at Hacettepe University
Faculty of Medicine, Department of Paediatric Neurology,
Ankara, Turkey 06100.
E-mail: banlar@hacettepe.edu.tr

A male and female with juvenile metachromatic
leukodystrophy (MLD) with unusual manifestations are
presented, each involving a novel arylsulfatase A gene
mutation. One patient demonstrated acute intermittent
encephalopathic episodes for 1 year after having received the
diagnosis of MLD at the age of 6 years. The other patient
presented at the age of 5 years with acute hemiparesis, which
was diagnosed as acute disseminated encephalomyelitis and
resolved in 3 weeks. After 2 years of remission he started to
show progressive neurological deterioration. The episodic
manifestations in both patients were associated with acute,
resolving cerebral lesions on magnetic resonance imaging
accompanying or preceding the classical demyelinating
lesions of MLD. The diagnosis of MLD was based on
arylsulfatase A enzyme activity levels and genetic analysis,
and after the exclusion of neurological conditions such as
encephalitis, vasculopathy, or mitochondrial disorders. The
pathogenesis of this previously undescribed finding in MLD is
unknown but might be related to a susceptibility of myelin to
acute damage.

See end of paper for list of abbreviations.

Metachromatic leukodystrophy (MLD) follows an invariably
progressive course after onset. We present two cases of juvenile MLD with acute, resolving cerebral lesions in addition to
the classical demyelinating lesions of MLD, and discuss possible underlying mechanisms.
Case report
PATIENT 1

A previously healthy 6-year-old female, single child of nonconsanguineous parents, presented with gait disturbance of
45 days. A wide-based gait, diminished patella and ankle
reflexes, extensor plantar responses, and slight tremor on
finger-to-nose test were observed. Nerve conduction velocity
was diminished on electroneuromyography. Cerebrospinal
fluid (CSF) contained elevated protein but no cells.
Arylsulfatase A (ARSA) activity was 9nmol/s/mg protein
(normal range 50–990nmol/s/mg protein). Magnetic resonance imaging (MRI) showed symmetrical T2 hyperintensities involving the periventricular and deep white matter and
corpus callosum representing demyelinization, and T2
hypointense stripes within the abnormal white matter, representing preserved areas (Fig. 1).
The symptoms showed little progression for 1 year. She
then started to experience relapses and remissions, beginning
with left focal seizures associated with right frontotemporal
discharges on electroencephalogram. CSF findings were

Developmental Medicine & Child Neurology 2006, 48: 383–387 383

unchanged. MRI showed a right, contrast-enhancing occipital
lesion involving cortex and subcortical white matter (Fig. 2).

Figure 1: Bilateral hyperintense cerebral white matter on
transverse T2-weighted turbo spin-echo (TR/TE;
5170/115ms) image.TR,time to repeat; TE, time of echo.

She was treated with acyclovir for a presumed diagnosis of
encephalitis and recovered in 10 days. However, 2 days later
she was readmitted with diplopia, headache, and vertigo, followed by loss of consciousness and anisocoria within 12
hours. On cranial MRI the right occipital lesion had disappeared; instead, the pons, red nuclei, and pyramidal tract in
the mesencephalon had increased T2 signal intensity (Fig. 3a)
with intense contrast enhancement (Fig. 3b). Routine laboratory investigations, CSF and serum cultures, and viral antibody titres were negative except for high CSF protein
(178mg/dl). She was treated with anticonvulsant and antiviral
drugs, and returned to her clinical baseline in 42 days.
Three episodes of vomiting, ataxia, tremor, or left hemiparesis, each lasting 1 to 2 weeks, occurred within 1 year,
with no intercurrent infection, medication, or other systemic
factors. Further metabolic tests, including serum and CSF
lactate levels, urinary organic acids, and mutation analyses
for mitochondrial diseases, were negative. On the next MRI
obtained 5 months after the first episode, red nuclei abnormalities of previous MRI had disappeared, but swelling and
T2 hyperintensity localized to the right cerebral peduncle,
together with new T2 hyperintensities in the right thalamus,
posterior limb of the internal capsule, and basal ganglia had
appeared. These recent lesions resolved again with partial
clinical recovery. MRI findings were consistent with MLD: T2
signal abnormalities with stripes in periventricular white
matter, centrum semiovale, and corpus callosum remained
unchanged during a further 2-year follow-up.
The ARSA gene was analyzed by using allele-specific amplification refractory mutation system (ARMS) assays for several
common MLD alleles and the pseudodeficiency (PD) allele,
followed by nucleotide sequence analaysis of the exons and

a

b

Figure 2: A hyperintense lesion. (a) T2-weighted turbo spin-echo (TR/TE; 4000/100ms) image; (b) contrast enhancement on
T1-weighted spin-echo (TR/TE; 550/15ms) image on right occipital cortex.TR, time to repeat; TE, time to echo.

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Developmental Medicine & Child Neurology 2006, 48: 383–387

exon/intron boundaries (Eng et al. 2003). The proband was
shown to be a compound heterozygote for the c.1277C>T
(p.Pro426Leu) MLD mutation and a complex deletion/insertion mutation in exon 8 (c.1268_1278delATGAGCCCC
CGinsCCCCCCCC; Fig. 4). The c.1277C>T (p.Pro426Leu)

missense mutation is a common MLD allele associated predominantly with juvenile and adult forms of MLD (Polten et al.
1991). The second mutation, which has not previously been
reported, changes the amino acid sequence of residues 423 to
426 from His-Glu-Pro-Pro to Pro-Pro-Pro. Presumably, this

a

b

Figure 3: (a) Transverse T2-weighted turbo spin-echo (TR/TE; 5170/115ms) image showing swollen and hyperintense midbrain; (b) postcontrast T1-weighted spin-echo (TR/TE; 650/20ms) image showing intense enhancement of red nuclei.
TR, time to repeat; TE, time to echo.

a

b
422
424
426
420
SerLeuThrAlaHisGluProLeuLeu
GCTCTCTGACTGCTCCCCCCCCCCTGCTC c.1277C>T
GCTCTCTGACTGCTCATGAGCCCCTGCTG
SerLeuThrAlaProProProLeuLeu
420
422
424
426

del/ins

430
428
426
424
422
L e u A s p Ty r L e u L e u L e u P r o G l u H i s A l a
CAGGTCATAGAGCAGCAGGGGCTCATGAGC
CAGGTCATAGAGCAGGGGGGGGGGAGCAGT
L e u A s p Ty r L e u L e u P r o P r o P r o A l a T h r
430
428
426
424
422

c.1277C>T
del/ins

Figure 4: Nucleotide sequence of patient 1 showing compound heterozygosity for c.1277C>T and
c.1268_1278delATGAGCCCCCGinsCCCCCCCC mutations. (a)Forward and (b) reverse sequences are shown. Sequence
analysis confirmed that each of the proband’s parents are heterozygous for one of these mutations (not shown).

Case Report

385

alteration would reduce or abolish ARSA activity. This is a conserved domain within which several other missense mutations
have been reported in patients with MLD, including
p.Pro426Leu (Polten et al. 1991), p.Leu428Pro (Regis et al.
1997), p.Pro425Thr (Marcão et al. 1999), and p.Tyr429Ser
(Eng et al. 2003).
PATIENT 2

Patient 2, a male currently 11 years old, presented at the age
of 5 years with a 1-day history of left hemiparesis. Cranial MRI
showed a T2-hyperintense, non-enhancing edematous lesion
in the right centrum semiovale (Fig. 5a) that resolved significantly 3 weeks later (Fig. 5b) and was interpreted as being
compatible with an acute demyelinating lesion, probably
acute disseminated encephalomyelitis (ADEM). He was discharged with complete resolution of hemiparesis. Preschool
psychometric evaluation with the Stanford–Binet test
revealed normal IQ. Attention deficit, hyperactivity, impaired

a

short-term memory, and visual perception noticed during his
first years at school were interpreted as sequelae of ADEM.
Two years later his parents complained about diminishing
school performance. The Wechsler Intelligence Scale for
Children–Revised revealed a total IQ score of 50. Cranial MRI
at that time demonstrated bilateral symmetrical periventricular T2 hyperintensities extending to centrum semiovale (Fig.
5c). ARSA activity was 1.5nmol/s/mg protein, confirming the
diagnosis of MLD. A more detailed family history revealed a
degenerative disorder in a paternal uncle who had died at the
age of 29 years. Parents were second cousins. The patient is
currently being followed-up clinically and shows slow intellectual and motor deterioration.
Comprehensive sequence analysis demonstrated that the
proband is homozygous for a missense mutation that alters
amino acid residue 391 (Fig. 6). Position 391 is polymorphic in
the normal population, with the two common alleles being
Thr (ACT) and Ser (AGT; Polten et al. 1991). The mutation in

b

c

Figure 5: Large edematous lesion in right centrum semiovale. (a) T2-weighted turbo spin-echo (TR/TE; 3800/105ms) image;
(b) T2-weighted images obtained 3 weeks later, in which lesion has resolved; (c) 4 years after first episode, T2-weighted
imaging revealed diffuse demyelination of centrum semiovale.

a

b
393
393
391
389
387
385
Ly s G l y G l y A r g Va l A l a P h e Va l G l y
CTTTCCACCCCGCACAGCAAAAACCCC

391

389

387

385

Ly s G l y S c r A r g Va l A l a P h e Va l G l y
CTTTCCACTCCGCACAGCAAAAACCCC
AGT
THR

Figure 6: (a) Reverse nucleotide sequence of patient 2 showing homozygosity for c.1071A>G mutation; (b) reverse nucleotide
sequence of an unaffected individual who is heterozygous for common polymorphism at residue 391 (Ser or Thr). Sequence
analysis confirmed that both parents of patient 2 are heterozygous for this mutation (not shown).

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Developmental Medicine & Child Neurology 2006, 48: 383–387

the proband changes residue 391 to Gly (GGT) and is most
probably due to a single base change (c.1071A>G) on an
allele having Ser at position 391. This mutation has not previously been reported in patients with MLD, nor have we
observed it in normal healthy samples (n>100).
Discussion
Juvenile MLD manifests between 4 and 12 years of age and,
despite some phenotypic variation within and between families, shows a relentlessly progressive course (Haltia et al. 1980,
MacFaul et al. 1982). Relapsing–remitting MLD has been
reported in a 48-year-old patient but not in children (Sadeh et
al. 1992). Certain leukodystrophies can present with acute
symptoms and signs after infection or trauma; however, remissions are unexpected (McGuinness et al. 1996). Patient 1 had
an unusual course, with exacerbations and remissions. The
first exacerbation was interpreted as encephalitis, or an
autoimmune reaction or metabolic decompensation triggered
by an infection. Enhancing deep gray and white matter lesions
were seen in another relapse for which no triggering factors
were detected. Those additional findings were dynamic: they
fluctuated in correlation with clinical status. The interpretation
of MRI included a toxic–metabolic process; however, exogenous toxins were unlikely in view of the history and the protracted clinical course, and investigations for endogenous
metabolic toxins or mitochondrial disorders were unrevealing.
Patient 2 showed an acute attack with well-documented resolution before classical findings were established. Again, MRI
findings subsided with remission, to evolve to typical MLD
lesions and clinical course. The first episode might have represented an initial manifestation of MLD; however, strict unilaterality and clinical and radiological remission contradict this
possibility. In the absence of diagnostic tests for ADEM, this disorder cannot be eliminated for the first episode. It is unknown
at present whether the myelin in a preclinical MLD patient is
more susceptible to autoimmune attacks.
Our cases suggest that juvenile MLD may present with atypical, sometimes episodic, symptoms and findings. The relation between these clinical findings and the novel mutations
remains to be confirmed in other patients.
DOI: 10.1017/S001216220600082X

Accepted for publication 25th August 2005.
Acknowledgements
We thank the families of these patients for their consent for
publication. These cases were part of a presentation at the American
Society of Neuroradiology Meeting 2004, Seattle, USA. Diffusionweighted imaging findings of these patients were published as part
of Oguz et al. (2004).
References
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A (ARSA) gene mutations in patients with metachromatic
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List of abbreviations
ADEM
ARSA
CSF
MLD

Acute disseminated encephalomyelitis
Arylsulfatase A
Cerebrospinal fluid
Metachromatic leukodystrophy

European Academy of Childhood Disability

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Case Report

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